Prostaglandin E.sub.2 (abbreviated as PGE.sub.2) has been known as a metabolite in the arachidonate cascade. It has been known that PGE.sub.2 possesses cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awakening effect, a sleep-inducing effect (an awakening effect or a sleep-inducing effect may occur according to the action site of PGE.sub.2.), a suppressive effect on gastric acid secretion, hypotensive activity and diuretic activity etc.
In the recent study, it was found that PGE.sub.2 receptor was divided into some subtypes which possess different physical role from each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3 and EP4 (Negishi M. et al, J. Lipid Mediators Cell Signalling 12, 379-391 (1995)).
The present inventors have studied to find the compound which can bind to each receptor specifically, have found that the compound of the present invention of the formula (I) can bind to EP4 subtype receptor strongly, and then have achieved the present invention.
The compounds of the present invention of the formula (I) can bind EP4 subtype receptor strongly, so they are useful for the prevention and/or treatment of immunological diseases (autoimmune diseases such as ALS, multiple sclerosis, Sjoegren's syndrome, chronic rheumarthrosis and systemic lupus erythematosus etc. and rejection after organ transplantation etc.), asthma, abnormal bone formation, neuronal cell death, liver damage, nephritis, hypertension, myocardiac ischemia and sleeping disorder etc.
Among the compounds of the present invention of the formula (I), compounds which bind weakly to receptor subtypes except for EP4 receptor do not express other effects and therefore such compounds are expected to be an agent having less side effect.
On the other hand, a lot of prostaglandins in which carbon atom at 7th position in PG skeleton was replaced with sulfur atom have been known. For example, some patent application related to such compounds are listed as follows:
In the specification of Japanese Patent Application Kokai Sho 57-108065, it is disclosed that the following compounds are useful as platelet aggregation inhibitor.
I.e. 7-thiaprostaglandin derivative of the formula (A) ##STR3## (wherein R.sup.1A is hydrogen, lower alkyl or pharmaceutically acceptable cation,
In the specification of Japanese Patent Application Kokai Sho 58-148857, it is disclosed that the following compounds are useful as platelet aggregation inhibitor.
I.e. 7-thiaprostaglandin derivative of the formula (B) ##STR4## (wherein R.sup.1B is hydrogen or C1.about.C10 alkyl, 5.about.6-membered alicyclic ring or phenyl,
In the specification of Japanese Patent Application Kokai Sho 58-110562, it was disclosed that the following compounds are useful for control of vascular action.
I.e. 7-thiaprostaglandin derivative of the formula (C) ##STR5## (wherein G is --COOR.sup.8C, --CONR.sup.9C R.sup.10C or --CH.sub.2 OR.sup.11C,
The above prior arts related to the compounds of the formula (A) and (B) show that these compounds in which carbon atom at 7th position of PG-skeleton are replaced with sulfur atom are useful as platelet aggregation inhibitor and that they are hard to be metabolized. Similarly, the above prior art related to the compounds of the formula (C) shows that these compounds are useful for control of vascular action.